Wnt5a-induced exosomes from bone marrow mesenchymal stem cells regulates immune cells via the NF-KB pathway, influencing neural stem cell proliferation and differentiation to promote spinal cord injury repair.

Spinal cord injury (SCI) remains a devastating neurological disorder with limited treatment options. Among emerging therapeutic strategies, the transplantation of mesenchymal stem cell-derived exosomes (MSC-Exos) has shown great promise owing to their functional consistency with donor cells, low immunogenicity, and suitability for various delivery routes. Wnt5a, a non-canonical Wnt ligand, has been reported to promote neuronal differentiation and spinal cord regeneration. However, its mechanistic role when delivered via exosomes (Exos) remains unclear. In the present study, the function and underlying mechanism of Wnt5a in promoting neuronal differentiation and spinal cord repair were investigated using bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in both in vitro and in vivo models. Our results demonstrated that Wnt5a-enriched BMSC-Exos significantly enhanced the proliferation and neuronal differentiation of neural stem cells, while suppressing astrocyte formation. High-throughput RNA sequencing revealed an association between Wnt5a and the nuclear factor-kB (NF-kB) signaling pathway. Intervention with lipopolysaccharide confirmed that Wnt5a exerts a suppressive effect on this pathway. In vivo, the transplantation of Wnt5a-modified BMSC-Exos facilitated the polarization of microglia toward an anti-inflammatory M2 phenotype, promoted neurogenesis, reduced astrocyte accumulation, improved spinal cord tissue architecture, and led to better motor function recovery. Collectively, these findings indicate that Wnt5a enhances the neuroregenerative potential of BMSC-Exos by modulating immune responses and suppressing neuroinflammation, likely through inhibiting the NF-kB signaling pathway. This strategy may offer a promising avenue for treating SCI.